The cephalosporin antibiotic known as cefazolin is represented by the following structural formula. ##STR1##
Cefazolin, U.S. Pat. No. 3,516,997 has achieved clinical importance and is widely used in the treatment and control of infectious diseases. Cefazolin sodium, cefazolin of the above formula in the sodium salt form, is administered parenterally.
This invention relates to a process for preparing cefazolin sodium as the crystalline monohydrate. In particular, this invention provides a process for preparing the crystalline monohydrate of cefazolin sodium substantially free of other crystalline forms. Various crystalline forms of cefazolin sodium have been described. For example, K. Kariyone, et. al., The Journal of Antibiotics, Vol. XXIII [3], 131-135, March, 1970, describes a pentahydrate designated as an .alpha.-form, and a .beta.-form containing 1.5 mole of water of crystallization. Cefazolin sodium can also be used as a lyophilized powder or in an amorphous form.
In the manufacture of cephalosporin antibiotics it is highly desirable to produce consistently the same crystalline form of the antibiotic from batch to batch. Such consistency is difficult to achieve with some cephalosporin antibiotics, particularly when a certain crystalline form is desired and other crystalline forms of the same antibiotic are capable of formation in the process.
Among the crystalline forms of cefazolin sodium the monohydrate is highly desirable as the pharmaceutical form. The crystalline monohydrate has also been designated as the .beta.-form, however, it is distinct from the .beta.-form described by K. Kariyone et. al., supra. As noted above, the .beta.-form described by Kariyone et al. is a 1.5 hydrate while the crystalline form provided by the process of this invention is a monohydrate.
Prior to this invention the preparation of the monohydrate crystalline form of cefazolin sodium has been difficult to achieve with any consistency. Commonly, the preparation of cefazolin sodium in mixtures of the various hydrated forms occurs. Such preparations containing mixtures of crystalline forms are generally unsuitable for pharmaceutical use because of instability on storage and during handling in the manufacturing process. For example, the higher hydrates tend to lose water of crystallization and thus crystallinity. Also, the water lost from the higher hydrates tends to cause instability of the product on storage. Accordingly, there is a need for a method for preparing cefazolin sodium in a single pharmaceutically acceptable crystalline form.